Levorphanol is an analgesic compound of the fully synthetic morphinan class which includes an array of opioid and non opioid based drugs. First discovered in the 1940's in Germany, it is a potent opioid agonist which is used as an effective analgesic to treat moderate to severe pain (albeit, less frequently used than other opioids).
Levorphanol is available in the form of the tartrate salt, and currently is marketed solely by US based Roxane Laboratories, as small tablets for oral use - with single doses of 2mg.
Levorphanol can be snorted intranasally or prepared for parenteral use via the various injection routes.
Levorphanol may be effectively implemented into a long term narcotic regimen as an alternative for use in opioid rotation protocols; i.e. the periodic conversion from one opioid to another over weeks or months of treatment for chronic pain. Like methadone, levorphanol has an incomplete cross tolerance with morphine, and is an appealing choice in patients who developed tolerance to high doses of morphine and other opiates. In such cases - switching to opioids with incomplete cross tolerance allows a lesser dose of the new opioid to be used; with levorphanol, this is due to its higher affinity at kappa & delta receptors, and its secondary modes of action via NMDA antagonism, etc. Additionally, these high-dose chronic patients may benefit from the tolerance inhibiting properties of the drug.
Levorphanol is a synthetic narcotic of the morphinan series, and therefore shares the phenanthrene molecular base structure of opium/opiate-derivates. Levorphanol is a stripped down analogue of morphine; without an ethylene chain, 7-8 double bond, or 6- hydroxyl group - Its structure is among the most simple of the phenanthrene opioid class. Levorphanol is the left-handed stereoisomer of the chiral compound racemorphan (or 'morphanol'). The dextrorotatory or (right handed mirror image) isomer, dextrorphanol, has no opioid properties, instead it acts at NMDA and sigma receptors.
Dextrorphanol is the main active metabolite of the antitussive drug dextromethorphan; which is a close relative of levorphanol - being the dextro stereoisomer to the opioid levomethorphan, the 3-methyl ether derivative of levorphanol. The chiral mix of dextro and levo - methorphan is racemethorphan (or simply 'methorphan', and possesses opioid and NMDA activities; as it comprises the pharmacological properties of both stereoisomers in a single compound.
Its modest molecular differences from morphine make the it roughly 5x more potent than morphine in vivo, being similar in strength (mg for mg) to hydromorphone when administered intravenously. 2-2.5mg levorphanol by the IV route is equianalgesic to 10mg morphine IV. The drug is well absorbed orally, with a bioavailabilty of roughly 50% or greater after oral use - 4mg levorphanol orally is equianalgesic to 30mg morphine via the same route.
Levorphanol acts as a potent agonist at the mu-opioid receptor - producing analgesia and euphoria similar to morphine. It also has a high affinity for kappa, and delta receptors; levorphanol is less subtype-selective than morphine and most other mu agonist opioids. Levorphanol is an NMDA receptor antagonist, and therefore blocks binding of the excitatory neurotransmitter glutamate (methadone shares this property as well). Its NMDA antagonism lends well to its efficacy in severe or resistant pain states, including neuropathic pain, which may respond poorly to first line opioids. NMDA antagonism inhibits the opening of post synaptic calcium channels, effectively blocking the cellular response of this "receiving line"; to put it simply, NMDA antagonists inhibit excitatory communication between neurons. This is believed to play a modulatory role on the development of opioid tolerance; possibly in part due to its regulation of synaptic plasticity. Research has shown that coadministration of an NMDA antagonist alongside morphine will reduce the development of tolerance compared to that of morphine alone, while allowing lower doses of opioid. Aside from its diverse action at opioid receptors and its NMDA antagonism, levorphanol is a serotonin and norepinephrine reuptake inhibitor, and therefore serves to enhance descending pain modulatory pathways which project to the spinal level; which further potentiates opioid mediated analgesia.
Levorphanol is rapidly absorbed long acting. Systemic peak levels of the drug are reached after 1 hour with oral use. Half life of the drug is 11 to 16 hours, and when taken on a regular basis, steady state should be acheived within 2 to 3 days. Due to the long half life, repeated doses will accumulate; thus plasma levels of levorphanol with chronic use can reach 5x those seen with a single use. This significantly reduces dosing requirements in chronic users. A similar effect is observed in methadone users.
Care must be taken with chronic use in those with kidney impairment; levorphanol's glucoronidated metabolite is excreted renally, and will accumulate with repeated use.
EFFECTS & SIDE EFFECTS
Levorphanol produces effects which are qualitatively similar to both morphine and methadone. Analgesia lasts 6 to 8 hours, in some cases longer - in contrast to the continuous 3-4 hourly dosing often required with morphine and similar drugs. Though a molecular analogue of morphine, the drug shares a number of properties with methadone (NMDA antagonism, long half life, similar systemic accumulative effect with repeat dosing).
Side effects of levorphanol are similar to those of mu-agonist opioids - sedation, miosis, respiratory depression, constipation, nausea & vomiting, urinary retention, inhibition of libido, pruritis with itching, and development of tolerance + dependence may all occur with levorphanol. Users however report less emesis and pruritis than with morphine.
Subjective effects of levorphanol are reported to be very pleasant, those most apparent being strong analgesia, anxiolysis & relaxation, a sense of well being with pronounced euphoria, increased sociability, a sense of energy, positive general outlook and mood, and a sense of motivation & desire for productivity. Levorphanol is antecdotally reported to be superior to most common opioids as a euphoriant, and is thoroughly effective in relieving severe and debilitating pain against which typical opioids may not be effective. Reports seem to conclude that the subjective effects of levorphanol are better pronounced than morphine's effects - the drug is said to take effect gradually after 30 to 60 minutes when taken orally; and described as producing an extended period of smooth and steady narcosis (characterized by an blissful opioid warmth and bright mood) which gradually dissipates over hours often very subtly. Many report it to be similar to methadone in its subjective effects.
Due to its limited use, a great deal of subjective reports are unavailable, making it difficult to reach a somewhat solid-impression regarding its value of this as a euphoriant or antidepressant.
We can however conclude that levorphanol is a potent synthetic narcotic with clinical and casual properties which are essentially equivalent to morphine, including a morphine-equivalent dependence liability, similar physiological side effects and a spectrum of typical mu-mediated euphorigenig & analgesic effects.
Levorphanol may be synthesized in a clandestine setting, likely by hobbyists and recreational/habitual opioid users.
Guides for synthesis are available with one in particular being popular among the underground circles of chemists
Relative Benefits of Levorphanol (as an analgesic)
One can speculate that levorphanol is superior to morphine in many respects, including:
A low capacity to induce tolerance
An enhanced action on descending inhibitory pathways
Its multi-modal synergystic properties
Actions against hyperalgesia
Its applicability to severe chronic pain including cancer-related and neuropathic pain.
Its Pharmacodynam Mechanisms of Action (A lower numerical value indicated a higher binding affinity for a particular site)
Very high affinity mu agonist - 0.21nM
High affinity kappa agonist - 2.3nM
Moderate affinity delta agonist - 4.2nM
High affinity NMDA antagonist - 0.6uM (methadone is 6.0uM, ketamine is 0.8uM)
5HT (i.e. serotonin) reuptake inhibitor (enhances spinal modulatory pathways)
Norepinephrine reuptake inhibitor (enhances spinal modulatory pathways)